Inhibitory Recognition and Signaling Inhibitory Receptors for MHC Class I
Multiple families of receptors in mouse and human recognize MHC class I products and transmit inhibitory signals when engaged. CD94 NKG2 receptors are heterodimers of C-type lectin type II transmembrane proteins that recognize the nonclassical MHC class I molecules HLA-E human leukocyte antigen-E, in human and Qa-1b in mouse Borrego et al. 1998 Braud et al. 1998 Lee et al. 1998 Vance et al. 1998 . Of the NKG2 family members that associate with CD94 including NKG2A, C, and E , NKG2A contains...
The NK Receptor Complex
Natural killer NK lymphocytes are potent effector cells that, unlike T lymphocytes, are able to lyse targets in the absence of a priori stimulation. Notably, NK cells do not represent indistinct killers because they are equipped with a large array of surface molecules that allow them to discriminate between normal cells and potentially dangerous targets. NK cells express MHC class I MHC I -specific receptors that after recognition of ligands on surrounding normal cells inhibit the NK-mediated...
Polymorphism of MIC and Disease Associations
MICA and to a lesser extent MICB are polymorphic, comprising more than 50 and about 15 amino acid substitutions in their extracellular a1a2a3 domains, respectively Stephens 2001 . Unlike MHC class I alleles, all these substitutions are only biallelic and appear randomly distributed. Little is known regarding the functional significance of this allelic variation however, many substitutions are not conservative, suggesting evolutionary selection instead of random fixation. Mapping onto the MICA...
B4
2B4 CD244 is a receptor with divergent functional properties that is present on all murine NK cells as well as a subset of T cells 111, 124 . In humans, 2B4 has been detected on NK cells, T cells, basophils, and macrophages 124 . Murine 2B4 receptors are predominantly inhibitory in nature, because mouse NK cells lacking 2B4 show enhanced cytotoxicity 96, 119 . On the other hand, human 2B4 appears to be predominantly an activating receptor, because human NK cells are more cytotoxic toward target...
Introduction on Dendritic Cells
This chapter discusses the interaction of NK cells with the professional antigen-presenting cells of the immune system, the dendritic cells DC , in regulating both innate resistance and adaptive immunity. DC are antigen-presenting cells, cornerstones between pathogen entry and lymph nodes that quickly respond to foreign antigens. Located in peripheral organs, skin, and mucosal surfaces, DC sample the environment for self and foreign material 1 . However, after antigen uptake DC, in order to...
KIR Contribution to MaternalFetal Bonding
The most prominent leukocyte in the uterine mucosal lining during pregnancy the decidua is a distinct population of NK cells that make close contact with invading fetal extravillous trophoblast EVT cells for reviews of NK cell biology during pregnancy, see Moffett-King 2002 Trundley and Moffett 2004 . Entry of fetal EVT into the decidua and walls of the maternal spiral arteries ensures the essential exchange of nutrients and gases between the maternal and fetal circulations. Activation of...
KIR Effects in Autoimmune and Inflammatory Diseases
Historically, the most robust disease associations with the highly polymorphic HLA class I class II loci have been autoimmune in nature, and only very few infectious diseases have shown strong, consistent HLA associations Cooke and Hill 2001 Gao et al. 2001 . It would not be surprising if the strongest effects of KIR variation were also observed in autoimmune diseases. Some previously determined HLA associations with autoimmune diseases might actually be explained by synergistic interactions...
KIR Promoters
To date, there are only a few reports that provide a detailed functional analysis of KIR promoters. The analysis of the promoter regions of the 2DL4 and 3DL1 genes revealed significant differences in promoter structure and function, consistent with the distinct expression patterns of these genes Stewart et al. 2003 . All NK cells transcribe the 2DL4 gene, whereas 3DL1 is expressed in a variegated fashion in NK cell subsets. DNAse I footprinting was used to identify several sites of protein...
Kir2dl4
KIR2DL4 CD158d is an intriguing NK cell-activating receptor that is up-regulated on IL-2-stimulated NK cells and contains both a transmembrane arginine and a cytoplasmic ITIM 55, 84,135 . In contrast to most other NK cell-activating receptors, KIR2DL4 is very effective at stimulating IFNy secretion but induces only weak cytotoxicity in resting NK cells 84,135 . The ITIM sequence in KIR2DL4 was found to be strongly inhibitory in isolation, as assessed in a chimeric receptor construct in which...
CD94 and the NKG2 Receptor Family
Whereas a single gene encodes CD94 23,103 , NKG2 is comprised of a multigene family, including the Nkg2A, C, E genes in human 48 , and Nkg2a, c, e in mice 47, 69 . The CD94 protein has a short cytoplasmic domain with no apparent functional motifs. Mouse NKG2A has a single immunoreceptor tyrosine-based inhibition motif ITIM in its intracellular region 47, 69 , which recruits tyrosine phosphatases such as SHP-1, providing inhibitory function to the heterodimer. By contrast, when NKG2C is...
A Challenge for the Future Understanding the Integration of Signals by NK Cells
Although the reductionist analysis of NK cell signaling is rapidly leading to a detailed knowledge of individual pathways, it is essential to reconstruct the complexity of NK cell signaling and establish how these different components are integrated. In one experimental system, NK cell cytotoxicity has been tested against individual ligands expressed on a Drosophila insect cell line or directly coupled to beads Barber et al. 2004 . Remarkably, this approach has shown that expression of ICAM-1...
The Regulation of NK Cell Function by CD2 Family Members 2B4 CD244
Of the receptors discussed in this review, 2B4 CD244 is the best characterized with respect to NK cell function. It is expressed on NK cells, CD8 activated T cells, y6 T cells, monocytes, basophils, eosinophils, and mast cells Boles et al. 2001 Kubota 2002 Munitz et al. 2005 . In mice, 2B4 has two isoforms generated by alternative splicing. 2B4-long has four ITSMs, and 2B4-short has one ITSM human 2B4 is only found as the long form Boles et al. 1999 Stepp et al. 1999 . CD48, the ligand for 2B4,...
DCNKCell CrossTalk During Infectious Diseases
NK cells have been widely proposed to play a role in the resistance to viral infection in both patients and experimental animals, in particular those induced by herpesviruses, hepatitis viruses, and HIV 65, 66 . A critical role for NK cells in mice in the defense against MCMV infection has been clearly demonstrated 67 . The NK cell-mediated cytolytic functions against infected cells are essential in the spleen, and a critical role for cytokine and chemokine released by NK cells has been...
NK Cell Priming by DC in Lymph Nodes
Unlike in peripheral blood and spleen, the presence of NK cells in lymph nodes LN has been controversial. However, recent data have shown that numerous NK cells are located in LN around B cell follicles in the T cell area in close vicinity with DEC205 DC 43 . Most of NK cells in LN are CD56bright CD94 NKG2A NKG2D 44, 45 , but unlike circulating NK cells they are noncytotoxic and perforin negative and do not express KIRs, CD16, and other NCRs NKp30 and NKp46 43 . The total number of LN NK cells...
Association of AP1 SP1 and Ets with NK CellSpecific Promoters
It is of interest to note that the core promoter regions of several NK cell-specific receptor genes contain potential Ets binding sites together with SP-1 or AP-1 binding sites. AP-1 plays a major role in the NK cell-specific transcription of the human 2B4 gene Chuang et al. 2001 , and AP-1 sites are found together with an Ets site in the NKG2A and NKR-P1C upstream promoters as well as the proximal CD94 promoter and Ly49g Pro3. The major NKR-P1C promoter used by mature NK cells contains Ets and...
Signals Downstream of ITAMs
The ITAM is characterized by an amino acid sequence of Yxx L I V x 6-8 Yxx L I V 71 . When a receptor associated with an ITAM containing accessory protein binds to its ligand, the tyrosine residues in the ITAM become phosphorylated by a Src family kinase e.g., Lyn, Lck, or Fyn . It is believed that this important phosphorylation event is primarily initiated by ligand interaction-mediated recruitment of these receptor-associated domains into lipid rafts at the c-SMAC, where Src family PTKs are...
Receptors
The Natural cytotoxicity receptors NCR family includes three Ig-like molecules termed NKp46 CD335 , NKp44 CD336 , and NKp30 CD337 10 selectively expressed by all NK cells. In particular, NKp46 and NKp30 are present on both resting and activated NK cells, whereas NKp44 is acquired only on activation, its expression at the cell surface correlating with the acquisition of optimal cytolytic activity by activated NK cells. NCR associate with ITAM-containing polypeptides such as CD3Z and Fcy NKp46...
The Host NK Cell Receptors of MHC Class I
The primary effector mechanisms 11,44,60,78 of NK cells are cell-mediated cytotoxicity and cytokine in particular IFNy secretion 11, 44, 68, 78 . For target recognition, NK cells express multiple germ line-encoded cell surface activating or inhibitory receptors, which provide a fine balance of signals governing NK cell function and serve as detectors of abnormal cells 60 . NK cell inhibitory receptors survey tissues for expression of MHC class I molecules, which under normal conditions are...
The CD2 Family of Natural Killer Cell Receptors
Department of Pathology, Committee on Immunology, University of Chicago, 5841 S. Maryland Ave., S-315 MC3083, Chicago, IL 60637, USA vkumar bsd.uchicago.edu 2 CD2 Receptor Family Signaling andX-Linked Lymphoproliferative Disease 97 3 The Regulation of NK Cell Function by CD2 Family Members 99 3.2 CD2 3.5 NTB-A 3.8 CD 3.9 CD2 Receptors with Unknown Functions on NK Cells 108 4 CD2 Family Receptors and Abstract The CD2 family of receptors is evolutionary conserved and widely expressed on cells...
Negative Signaling by Inhibitory Receptors
NK cell tolerance toward normal cells is derived from negative signaling that originates through cell surface inhibitory receptors, which detect MHC-I molecules on the surface of normal cells. The MHC-I-binding inhibitory receptors expressed on NK cells include killer cell Ig-like receptors KIR human , Ly49 mouse , NKG2A CD94 human and mouse , and ILT2 LIR1 CD85j human . The engagement of NK cell inhibitory receptors with MHC-I molecules on normal target cells causes them to coaggregate with...
NK Cells Protecting from Disease
The regulatory role for NK cells in immune activation can be achieved either by skewing the immune response toward a Th1 or a Th2 response or by direct inhibition of the immune response. NK cells are capable of producing IL-10 along with IFN-y, and also immunoregulatory cytokines such as TGF- , although these properties of NK cells are much less well studied than the prototypic role of NK cells as IFN-y producers Gray et al. 1994 Peritt et al. 1998 . Furthermore, it has been suggested that NK...
KIR Defense Against Microorganisms
CD8 T cells serve a critical role in eliminating intracellular pathogens by detecting viral peptides in the context of MHC class I molecules on the surface of infected cells. Some viruses retaliate by disrupting cell surface expression of class I Tortorella et al. 2000 . But the competition ensues with the ability of NK cells to detect missing self Karre et al. 1986 and kill cells that express little or no class I ligands for inhibitory receptors on the NK cell. Indeed, NK cell inhibition...
Vav Rho Family GTPases and MAP Kinases
Vav proteins are major players in numerous downstream NK cell activation events and have been the subject of intense research in recent years. The Vav proteins are GEFs that activate certain Rho family GTPases by promoting the exchange of enzyme-bound GDP for GTP 45 . Rho family GTPases serve as molecular switches that are on when bound with GTP, but off when the nucleotide is hydrolyzed to GDP. The best-characterized subgroups of the Rho family are Rho three members , Rac four members , and...
Signaling Through DAP10
DAP10 is only associated with one activating receptor, which is NKG2D. Human NKG2D only associates with homodimers of DAP10, and murine NK cells possess a similar version, NKG2D-L, which also associates only with DAP10 dimers 50,65,140 . Murine NK cells, however, also express a shorter version, NKG2D-S, which lacks 13 amino-terminal amino acids in the cytoplasmic domain and can uniquely associate with homodimers of both DAP10 and DAP12 50,65,140 . In contrast to ITAM-signaling receptors, the...
Transcriptional Regulation of NK Cell Receptors
Basic Research Program, SAIC-Frederick, National Cancer Institute-Frederick, Bldg. 560, Rm. 31-93, Frederick, MD 21702-1201, USA 2 Ly49 Promoter 2.2 The Role of 2.3 Identification of Pro1, Pro2, and 2.4 Pro1 Is a Bidirectional Transcriptional 2.5 The Pro1 Probabilistic Switch 3 NKR-P1 4 CD94 5 NKG2A 6 KIR 7 Association ofAP-1,SP-1, and Ets with NK Cell-Specific Promoters 71 Abstract The stochastic expression of individual members of NK cell receptor gene families on subsets of NK cells has...
Regulation of NK Cell Activation by DC
Pioneering studies by Fernandez et al. showed that the DC growth factor Flt3-L, which promotes both DC and NK cell expansion, was also capable of promoting in nude mice a NK cell-dependent antitumor effect that could be significantly abrogated by treatment with an anti-CD8a mAb 27 . These experiments suggested a direct role for CD8a DC in NK cell triggering in vivo. This role was directly demonstrated by the adoptive transfer of the mouse DC cell line D1 into AK7 mesothelioma tumors, leading to...
References Mkl
1. Biron, C.A. et al. 1999 Natural killer cells in antiviral defense function and regulation by innate cytokines. Annu. Rev. Immunol. 17,189-220. 2. Parham, P. 2003 Immunogenetics of killer-cell immunoglobulin-like receptors. Tissue Antigens 62,194-200. 3. Moretta, L. and Moretta, A. 2004 Killer immunoglobulin-like receptors. Curr. Opin. Immunol. 16, 626-633. 4. Lopez-Botet, M. et al. 2000 NK cell recognition of non-classical HLA class I molecules. Semin. Immunol. 12,109-119. 5. Algarra, I. et...
Assembly and Signaling Properties of NKG2D and CD94NKG2 Receptors Expressed by
CD94, NKG2D, andthe NKG2 family comprisedofA, C, E, andFare genetically and structurally related type II transmembrane proteins with a C-type lectin domain. They are encoded within the NK complex NKC on human chromosome 12p12.3-p13.1 Houchins et al. 1991 Plougastel and Trowsdale 1997 Renedo et al. 1997 and overall display very low levels of polymorphism, CD94 and NKG2A being the most conserved Shum et al. 2002 . NKG2A and NKG2E have splice variants, NKG2B and NKG2E, respectively. The signaling...
Nkrpl and Clr Families
The NK1.1 Nkrp1c molecule is the best known serological marker on NK cells in C57BL 6 mice Ryan et al. 1992 . Lymphocytes that express the NK1.1 antigen and do not express the TCR receptor are generally considered to be bona fide NK cells Lanier et al. 1986 . Interestingly, some mouse strains such as BALB c, SJL, AKR, CBA, C3H and A do not express the NK1.1 antigen. Identification of NK cells in these strains relies on use of an integrin molecule DX5, expressed selectively on NK cells Arase et...
The ULBP Family of NKG2D Ligands
Binding studies utilizing recombinant IgG Fc region fusion proteins led to the discovery that the CMV UL16 transmembrane glycoprotein, which was of unknown function, specifically interacts with cell surface proteins that were termed ULBP1 and ULBP2 Cosman et al. 2001 . Three additional ULBP sequences were identified by sequence homology Fig. 2 Chalupny et al. 2003 Bacon et al. 2004 . ULBP3 and -4 and MICA do not interact with UL16, but MICB does. ULBP share no direct sequence relationship with...
Physical Parameters of NK Cell Activation The Cytolytic NK Cell Immune Synapse
The surface of contact between NK cell and target cell has been termed the NK immune synapse NKIS . Contact with a susceptible target cell has been named the cytolytic NKIS cNKIS , and a noncytolytic interaction with a normal cell is defined as an inhibitory NKIS iNKIS , which will be discussed later. Numerous activating receptor-ligand pairs and effector signaling molecules accumulate at the cNKIS, forming an aggregate called the central supramolec-ular activation cluster c-SMAC see Fig. 1 ....
NKRP1 Promoters
The NKR-P1C gene encodes the NK1.1 antigen expressed by all functional C57BL 6 NK cells and NKT cells Ryan et al. 1992 . This gene is also expressed early in development, because a CD117 , NK1.1 progenitor cell in thymus was shown to produce both NK and T cells Carlyle et al. 1997 . There is a general conservation of exon structure among the lectin-related genes, and the NKR-P1C gene was recently shown to possess three distinct promoter elements in locations similar to the three promoters...
MHC Class I Mimicry
A number of CMV genes encoding homologs of cellular gene products are thought to play a role in subverting the host immune response. A comparison of the complete MCMV genome sequence with published host sequences demonstrated the presence of gene products similar to cellular proteins, such as MHC class I proteins, T cell receptor delta chain, and G protein-coupled chemokine receptors 1,73,85 . Viral homologs of MHC class I molecules have been found in mouse, rat, and human and other primate...
NKG2 ReceptorMediated Regulation of Effector CTL Functions in the Human Tissue
Department of Pathology, University of Chicago, 5841 South Maryland Avenue-S354, 2 TCR and Activating NKRs The TCR Primacy Rule 140 3 Assembly and Signaling Properties of NKG2D and CD94 NKG2 Receptors Expressed by CTLs 142 4 Tissue LigandsofNKG2D and CD94 NKG2 Receptors 145 5 Regulation of NKG2D and CD94 NKG2 Expression and Function in CTLs 146 5.1 Role of Tissue 5.2 Role of TCR 5.3 Role of TCR 5.4 Role of IL-15 6 Role of NKG2D and CD94 NKG2 Receptors in Organ-Specific Abstract NKG2 receptors...
Role of NKG2D and CD94NKG2 Receptors in OrganSpecific Autoimmunity
Whereas the role of KIR expression by CTLs is suggested mostly by genetic reports and studies performed on peripheral blood lymphocytes Martin et al. 2002 Momot et al. 2004 Namekawa et al. 2000 Snyder et al. 2003 Yen et al. 2001 , there is now strong, converging evidence indicating that NKG2D and CD94 NKG2 receptors play essential roles in the control of effector CTLs in tissues, controlling important disease processes. The presence of abundant melanoma-specific CTLs in patients with...
Structure and Regulation of MIC
MICA and MICB are encoded by genes near HLA-B, and homologous dysfunctional pseudogene sequences are located in the vicinities of HLA-A, -E, and -G Bahram et al. 1994 Bahram and Spies, 1996 . The 43-kD MICA and MICB core polypeptides share 84 amino acid sequence homology and are distinctively related to mammalian MHC class I chains as compared to the class I-like CD1 and Fc-receptor molecules encoded elsewhere in the genome. The MIC protein sequences are about equidistant from all mammalian MHC...
The Virusan Evolutionary Perspective
With its 230-kb double-stranded DNA genome, wide tissue tropism, strict species specificity, and ability to establish latency, MCMV is a typical member of the betaherpes subfamily of the Herpesviridae 85 Fig. 1a . Herpesviruses are considered an evolutionary success in terms of their occurrence in the animal kingdom because of their modest pathogenicity in the natural settings and their ability to establish latency. Part of this success can be attributed to the ability of herpesviruses to...
NKG2D and Its Physical Interactions with MIC and ULBP
Formerly an orphan receptor with unknown function Houchins et al. 1991 , NKG2D was first identified as a receptor for MICA and MICB and subsequently for the ULBP ligands Bauer et al. 1999 Cosman et al. 2001 Chalupny et al. 2003 Bacon et al. 2004 . Recombinant NKG2D binds firmly to trans-fectants expressing its ligands, as do recombinant ligands to lymphocyte subsets expressing NKG2D Steinle et al. 2001 . Analysis by size-exclusion chromatography showed that NKG2D homodimers form stable...
Downregulation of MHC Class I
Several HCMV and MCMV gene products prevent the translocation of MHC class I proteins to the cell surface 8 . Four HCMV-encoded glycoproteins are involved in this process US2, US3, US6, and US11 46 . They are all single transmembrane TM -spanning type I , immunoglobulin domain-bearing proteins of the US6 family, which probably arose by duplication of an ancestral gene. Binding of the US3 protein to MHC class I molecules causes their arrest in the endoplasmic reticulum ER 51 . On the other hand,...
KIR on Cancer
Loss of HLA class I molecules on tumor cells may evolve during tumorigenesis as a mechanism of tumor cell escape from T cell-mediated elimination Smith et al. 1989 Kaklamanis and Hill 1992 . Under such circumstances, inhibitory receptors for HLA class I on NK cells will be disengaged and activating receptors will dictate, leading to NK cell killing of the tumor cell target. Involvement of activating KIR in this defense mechanism is suggested by a recent study in which KIR2DS4 was shown to...
The Ly49 Receptor Family
The Ly49 gene family encodes both activating and inhibitory receptors, which are expressed as disulfide-bonded homodimers on subsets of NK cells in an overlapping pattern. The inhibitory receptors contain ITIMs in their cytoplasmic domains, whereas the activating receptors lack ITIMs and associate with the ITAM-containing DAP12 adapter protein 97 Fig. 2b . To date, three distinct strain-specific Ly49 haplotypes have been identified from the C57BL 6, 129Sv, and BALB c mouse strains 63, 72, 82...
DCNK Cell CrossTalk in Cancer
It is assumed that tumor cells are poorly immunogenic and not recognized by the immune system because proinflammatory signals required for DC activation are missing in vivo. However, NK cell activation, either spontaneously induced by the characteristics of the tumor cell transplanted e.g., MHC class I low, TAP deficient 80-82 or forced by overexpression on the tumor cells of NKG2D ligands 83,84 , CD27 85 , or gp96 86 , has been shown to promote the elicitation of cognate and protective immune...
The DCNK Cell Interplay in the Periphery
Other sites of DC-NK cell interactions could be inflamed tissues. The chemokine receptor repertoire of CD56dimCD16 blood NK cells expressing CXCR1 and CX3CR1 suggests that they could migrate in response to IL-8 and soluble fractalkine 51 . A direct contact between DC and NK cells was first shown in Malassezia-induced atopic skin lesions 52 and later highlighted in imatinib mesylate Gleevec STI571 -induced lichenoid dermatitis 53 . We recently observed aberrant PEN5 NK cell infiltrates in...
Role of MICNKG2D in Autoimmune Diseases
Because ligand binding unconditionally triggers NKG2D without counterbalance by a known antagonist, its dysregulation together with anomalous expression of MIC in local tissue sites may promote autoreactive T cell stimulation. Indeed, recent evidence indicates that MIC-NKG2D may play important roles in the pathogenesis of several autoimmune diseases. In rheumatoid arthritis RA , the severity of autoimmune and inflammatory joint disease correlates with large numbers of CD4 CD28- T cells, which...
CD85j ILT2 LIR1
The Ig-like transcript ILT or leukocyte Ig-like receptor LIR gene family flanks the KIR locus at chromosome 19p13.4, encoding for molecules preferentially expressed by the myeloid lineage Colonnaet al. 1999 . Some ILT LIR, CD85 molecules contain cytoplasmic ITIM that recruit SHP phosphatases, whereas others display a charged transmembrane residue Arg and associate to the FceR y chain. Among the first group, ILT2 LIR-1, CD85j and ILT4 LIR-2 broadly interact with HLA class I molecules Colonna et...
CD2 Receptor Family Signaling and XLinked Lymphoproliferative Disease
Receptors in the CD2 family have diverse signaling pathways that are not completely understood. The CD150 subfamily members have cytoplasmic ITSMs, which suggests that they have a common signaling pathway. By contrast, non-CD150 subfamily members, CD2, CD48, CD58, CD84-H1, and BLAME, lack tyrosine-based cytoplasmic signaling motifs. CD48 and an isoform of CD58 have GPI linkages that may signal by association with lipid raft domains and lipidraft-associatedkinases Stefanovaetal. 1991...